Category Archives: inflammatory bowel disease

Quality improvement and better outcomes in Pediatric Inflammatory Bowel Disease

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More information on outcomes and quality improvement (QI) efforts are available from Cincinnati Children’s Hospital (JPGN 2012; 55: 679-88).  The QI efforts at Cincinnati are part of a broader effort in QI in pediatric IBD that has been discussed on a previous post (see below).

Our group has rejoined Improve Care Now (ICN) and I look forward to gaining more first hand experience.  Some of the ICN target goals:

  • 80% remission rate among each center and sustained remission rate of 45%
  • 76% steroid-free remission
  • 90% checking TPMT if using thiopurine
  • 95% checking PPD/chest xray if using biologic therapy
  • 95% using accepted methotrexate dosing

As I look at these goals, I wonder whether the remission rate is feasible and about the variation in different centers. For example, among the groups with >75% enrollment of their patients, one center reports a 89% remission rate and another center 64% remission rate.  Given the limited number of therapeutic agents, how could there be such a difference?  Some explanations could include variation in the use of more potent biologic agents as well as capturing/assuring followup of more patients who are doing well.

Given this backdrop, I looked at this most recent publication to learn how their QI practices could translate into better care for my patients.

In this retrospective chart review study of 505 patients, who were followed from 2007-2010 at the IBD center, the remission rate increased from 59% to 76%.  The data were captured prospectively.  This corresponded to improved patient global assessment (>7) from 69% to 80%.  Repeated steroid use dropped from 17% to 10%.  Vitamin D (25-OH D) improved and this also correlated with quiescent disease.

Remission rates were defined by a pediatric Crohn clinical disease index, the sPCDAI, or PUCAI for Ulcerative colitis.

Key observations:

  • There was a trend towards increased use of anti-TNFα therapy (along with decreased use of 6-mercaptopurine) during the study period, but this did not reach statistical significance. No statistical difference was identified in the use of any major IBD medication class.
  • Despite target goals, the only drug class with a statistically significant change in dosing was 5-ASA (from 42 mg/kg to 50 mg/kg).
  • Fecal calprotectin monitoring increased.  The QI team recommended that IBD patients with ‘inactive’ disease have a fecal calprotectin measured every 6 months.  Those with elevated values had therapeutic drug monitoring implemented.  “Fecal calprotectin >400 μg/g is associated with a higher chance of relapse in a pediatric cohort.”
  • Starting in 2009, increased vitamin D monitoring was implemented (every 6 months).  In patients with a serum 25-OHD level < 30 ng/mL, treatment with 50,000 units weekly (for 6-8 weeks) was recommended (8000 units if weight <20 kg).  Once serum 25-OHD was >30 ng/mL, patients were maintained on monthly dosing.
  • Preclinic planning also increased and corresponded to improved remission rates which were 67% in 2009 and 76% in 2010.
  • The authors conclude: “Our results show that significant improvement in patient outcomes were achieved following QI efforts that did not rely on new medications or therapies, rather through initiating novel care processes and standardization of care.”

I think this conclusion is misleading.  First of all, as the authors point out, they did change their therapeutic approach.  They started vitamin D in more patients, used anti-TNFα therapy in more patients, and increased dosing of 5-ASA agents.  Other gains in remission rate could have been related to improved followup of patients who were doing well.

Despite my skepticism about the conclusion, I think the overall achievements are laudable.  Decreasing variation of care and assuring that all patients receive the best care possible with our diagnostic tests and current therapies is certainly worthwhile.  When patient care is studied carefully, this makes sure that “standard” practice like checking TPMT status before thiopurine use, checking PPDs before anti-TNFα therapy, and using optimal drug dosing occur in virtually all patients.

Developing a checklist for each patient can help assure that best practices occur.  For those with electronic medical records, this may mean putting in more “hard stops.”  A hard stop means the physician cannot sign out of a chart without paying attention to a specific detail.  For example, if a physician orders methotrexate, a “hard stop” could come up if the dosing was not in the typical target range.

Useful link:

Link for disease classification (quiescent, mild, moderate, severe):

http://links.lww.com/MPG/A129

Related blog entries:

Best strategy for dose escalation of infliximab

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At least 50% of patients with long-term infliximab therapy require dose escalation.  However, dose escalation can mean doubling the dose or shortening the infusion interval.  So which strategy is best?  A recent article provides some insight into this question (Inflamm Bowel Dis 2012; 18: 2026-33).

In this multicenter retrospective study of 168 Crohn’s disease (CD) patients, the outcome of patients who had dose-doubling (n=112) to 10 mg/kg/dose/8 weeks was compared with patients whose infusion intervals were halved to 5 mg/kg/dose/4 weeks (n=56).  The entire cohort had a mean age of 25 years and a mean disease duration of 12 years.  39% had a history of previous intestinal surgery.  Concurrent use of thiopurines was noted in 68% and concurrent use of methotrexate in 4%.

Sustained response at 1 year to dose-doubling strategy was 50% compared with 39% in the interval-halving group.  Favorable factors included nonsmoking status, normal C-reactive protein, and CD diagnosis between 16-40 years of age.

It is noted that a subsequent dose escalation was experienced by 28 of the 87 patients who had loss of response after first dose escalation.  Regained response occurred in 9 (32%) of this cohort.

The authors indicate that increasing the dose to 10 mg/kg/8 weeks is likely preferable due to convenience and cost.  At the same time, it is apparent that shortening the infusion interval is not likely to be more effective than dose doubling.

Related blog entries:

Does bone density improve with IBD therapy?

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Long term followup is needed to determine the significance of low bone mineral density (BMD) in children and adolescence with IBD; data with 2 year followup is available (JPGN 2012; 55: 511-18).

In this study from Sweden, 144 patients with IBD were enrolled and 126 were available at 2-year followup (2003-2005).  Among the 144 patients, there were 93 males and 83 with UC. Low BMD was noted in children with both UC and CD for the lumbar spine at baseline and no improvement was noted at 2 years.  Only boys had lower BMD z scores for the lumbar spine (LS) (-1.1); girls had normal LS z scores (0).

While the investigators could not demonstrate catch up in bone mineral density, they note that gains in BMD may accrue beyond late adolescence into early adulthood; this takes place after completion of linear growth.  In the subgroup of subjects in early adulthood, there was improvement in BMD:

  • For boys: from -1.7 at baseline (age 17.9) to -0.5 at followup (age 20.0)
  • For girls: from -0.4 at baseline (age 17.1) to 0.4 at followup (age 19.2)

With greater use of biologic therapy, these data are likely to change.  Among medical treatments, only biologic therapies have been shown to improve bone formation and improve catchup growth.

Related blog entry:

Additional references:

  • -JPGN 2011;53: 361. Similar prevalence of low Vitamin D as general population –58% with less than 32.
  • -JPGN 2011; 53: 11. Guidelines for low bone mineral density in IBD.
  • -JPGN 2009; 48: 538. Need to adjust bone density for bone age.
  • -Gastroenterol 2009; 136: 123. Longitudinal bone health study. Steroids did NOT adversely affect bones. n=78.
  • -Clin Gastro & Hep 2008; 6: 1378. IFX improves biomarkers of bone formation.
  • -J Pediatr 2008; 153: 454, 484. Use of biomarkers of bone turnover in Crohn dz; even when controlling for other factors like delayed bone age, delayed puberty, etc, still evidence of decrease bone formation and increased resorption.
  • -JPGN 2007; 45: 538. Ca/Vit D supplements -no change in BMD in IBD patients over 12 months.
  • -Clin Gastro & Hep 2007; 5: 721. DXA may not predict risk well.
  • -IBD 2007; 4: 416. Inflammation, not steroids, is key factor in bone mineral density.
  • -IBD 2006; 13: 42. Natural hx of bone mineral density in IBD; steroid dose did not correlate with BMD. Children did not have “catch up” bone density.
  • -JPGN 2006; 43: 597. Crohn’s patients had similar rate of fractures as siblings w/o IBD.
  • -Clin Gastro & Hep 2006; 4: 152. Osteoporosis in IBD.
  • -IBD 2006; 12: 797. Review of bone mineral density with IBD
  • -Clin Gastro & Hepatol 2005; 3: 113-121, 122-132 & editorial 110. In 1st article, budesonide better for bones than other steroids. In 2nd article, unable to show benefit of addition of etidronate to Ca++/Vit D.
  • -NEJM 2002; 351: 868. Intermittent steroids in nephrotic syndrome did NOT change bone mineral density.
  • -Gastro 2001; 121: 1485-88. Tanning bed Rx of vitamin D deficiency.
  • -Gastro 2000; 119: 639-46. Alendronate increases BMD in pts c Crohn’s
  • -NEJM 1998; 339: 292-9/ J Bone Miner Res 2000; 15: 1006-13. Bisphosphonates effective in steroid-induced bone disease

Monitoring TNF antagonists in inflammatory bowel disease

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Previously, this blog has discussed the use of drug monitoring in inflammatory bowel disease (Drug levels for inflammatory bowel disease | gutsandgrowth).  A good review of this topic has been published recently (Clin Gastroenterol Hepatol 2012; 10: 1079-87).

Some of the useful pointers:

  • Factors that influence clearance of TNF antagonists are reviewed:
  1. Antidrug antibodies (ADA) increase clearance and worsen outcomes
  2. Use of concomitant immunosuppressives reduces the likelihood of ADA formation and increase drug concentration.   In the SONIC trial, use of azathioprine was associated with trough infliximab (IFX) levels of 3.5 μg/mL compared with 1.6 μg/mL with monotherapy.  Also, ADA was reduce: 0.9% compared with 14.6% in the monotherapy group. [Other studies though have found variable effects of cotherapy.]
  3. Low serum albumin and high CRP are associated with increased drug clearance
  4. Individuals with high body size and males are more likely to have increased drug clearance.
  • Better assays for measurement of IFX and adalimumab (ADL) are now available.
  • Currently a trial evaluating trough levels is underway: Trough Level Adapted Infliximab Treatment (TAXIT).  With this study, the accepted target range for trough levels is 3-7 μg/mL.  Levels >7 μg/mL are considered supratherapeutic and allows for a prolongation of dosing interval.  Preliminary data confirm that trough levels inversely correlate with CRP.
  • Proposed algorithm in individuals with loss of response & positive ADA.  If ADAs present at high titer, then switch to different TNF antagonist.  If low  titer, could either switch or attempt drug escalation.
  • With IFX, when antibodies to infliximab (ATIs) are present, the likelihood of responding to increased dose is less than 20% whereas changing to different TNF antagonist has about an 90% response (in patients who were previous responders).
  • Proposed algorithm in individuals with loss of response & negative ADA.  If subtherapeutic trough levels (IFX ❤ μg/mL, ADL <8 μg/mL, or certolizumab <27.5 μg/mL), then dose escalation is worthwhile.  If drug levels are therapeutic, then dose escalation will not be effective.
  • With IFX, more than 85% of patients will respond to drug escalation when the trough level is subtherapeutic. This is much more favorable than switching agents.
  • One other issue with ADAs is that they may be transient is some patients.  Perhaps one-fourth of ATIs may be transient which may explain why some individuals with ATIs may still respond to dose escalation.

These points give several reasons why drug monitoring is useful in individuals with loss of response and may help determine whether patients responding to therapy may be able to prolong dose intervals.  At the same time, when an individual is not responding to therapy, it is also important to determine if in fact active inflammation is present with objective markers and to consider alternative explanations for GI symptoms (eg. Clostridium difficile infection, irritable bowel, bacterial overgrowth, etc.).

Related blog entries:

Only one chance to make first impression | gutsandgrowth

When nothing else is working | gutsandgrowth

Infliximab for children with Ulcerative Colitis | gutsandgrowth

Adalimumab for children with Crohn’s disease | gutsandgrowth

CHOOSE TNF TRIAL | gutsandgrowth

Testing worm therapy for chronic diarrhea/IBD in Monkeys

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Today’s blog is an excerpt from BBC News (Thanks to Ben Gold for the tip).  The full link:

BBC News – Parasitic worms ‘treat diarrhoea‘

“Chronic diarrhoea could be treated using parasitic worms, a study of monkeys has suggested. Research published in PLOS Pathogens, suggests the treatment restores gut bacteria to a healthy state. Other work in mice has already suggested conditions such as ulcerative colitis could be treated in this way. A UK expert said parasitic worms were being investigated for a range of conditions, including multiple sclerosis and allergies.”

Captivity

“Inflammatory bowel diseases, like colitis, are often fuelled by a wrongly targeted response by the immune system to gut bacteria. Such diseases are more common in developed countries – and scientists suggest this is because people in developing countries have more exposure to parasitic worm (helminth) infections and therefore have a natural protection that has evolved as people and worms learnt to co-exist.


Recent studies have used parasitic worms to successfully treat inflammatory bowel disease in humans, but it is unclear exactly how they do this.

This latest study looked at monkeys because young macaques kept in captivity often develop chronic diarrhoea that can be hard to treat. Five macaques with diarrhoea were treated with parasitic worms called whipworms. Tissue samples were taken before and after treatment and it was found the balance of gut bacteria was restored to required levels. And four out of five animals had less diarrhoea and started to gain weight.

Dr P’ng Loke, of the New York University Langone Medical Center, who led the study, said: ‘The idea for treating colitis with worms is not new, but how this therapy might work remains unclear.  Our findings suggest that exposure to helminths may improve symptoms by restoring the balance to the microbial communities that are attached to the intestinal wall.’

The researchers now plan a study in humans to look at how pig helminth eggs might help alleviate the symptoms of colitis.

Compensating

Prof Graham Rook, of the centre for clinical microbiology at University College London, said a number of research teams were investigating the effects of parasitic worms in various conditions. ‘This is not part of the hygiene hypothesis [which says exposure to bacteria strengthened the immune system]. It’s the “old friends” hypothesis. We co-evolved with these things, so they had to be tolerated. We found ways of suppressing the immune systems, and in some way have come to depend on them.’ And he said the field of research as a whole would be “hugely significant”.  He added: ‘With helminths, if you get the dose right, you can probably live with worms and not have symptoms. But it may well be there is going to be a battery of molecules you could be dosed with to compensate for not meeting our “old friends”.’

THE WONDER OF WORMS

  • Parasitic worms are “old friends” and humans have lived with them for as long as we have existed.
  • And while people in developing countries still do so – and have low levels of inflammatory disease, the opposite is true in developed countries.
  • It appears our immune systems came to rely on parasitic worm infections as part of the way our body defended itself.
  • And when they are no longer there, it appears that may upset our immune systems.
  • Now researchers are looking at how the worms’ effects can be harnessed to treat conditions ranging from multiple sclerosis to allergies.
  • Hookworms and pig whipworms are amongst those being investigated.
  • Results are promising.
  • But those squeamish about dealing with worms or their eggs may not have to worry – it is more likely drugs will be developed that mimic their effects.”

Additional references:

  • -Gastroenterol 2012; 142: 55.  Helminth infection (with enterobiasis) did not reduce risk of IBD in large population-based study (924,000 Danish database).
  • -Gastroenterol 2005; 128: 825. Trichuris suis for UC. 43% improved vs 17% of placebo. Only mildy effective.
  • -Gut 2005; 54: 87-90. Trichuris suis for Crohn’s
  • -Gastroenterol 2005; 129: 768-69. (letter re safety)
  • -NEJM 2010; 363: 1476-78. Interactions between Helminths and immunogenicity.

How new therapies impact colectomy in UC patients

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Has the need for colectomy changed with the increasing use of more potent medical therapies for ulcerative colitis (UC)?  One article gives some insight into this question (Inflamm Bowel Dis 2012; 18: 1641-46).

This French study followed 151 patients with newly diagnosed UC from 2000-2008; median followup was 58 months. During this time, 21 patients (14%) underwent colectomy.  1.3% required colectomy in the first year following diagnosis.

Looking closer at their study, 55% of patients had pancolitis.  Cyclosporin usage, typically given in refractory cases, was the only medication determined to be a predictive factor for surgery.

Medication usage during study period:

  • 68% oral mesalamine products
  • 72% systemic corticosteroids
  • 7% methotrexate
  • 49% azathioprine
  • 9% cyclosporin
  • 30% had received at least one anti-TNF agent

The authors concede several limitations, including the evolving nature of UC treatment.  Yet, they conclude that colectomy still is frequently needed and the use of IBD medications, including anti-TNF, “does not appear to reduce the long-term need for surgery in UC.”

I take issue with the last sentence.  Whether anti-TNF agents prove to be a disease-modifying treatment over the long-term is not known.  In this particular cohort, only 30% were even exposed to these agents.  My conclusion: we need a study designed to answer the question.  This would require larger numbers of patients followed prospectively for many years.

Related blog entries:

Ustekinumab for Crohn’s Disease

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Ustekinumab is emerging as an option for inflammatory bowel disease.  A study examining its effectiveness for TNF-refractory Crohn’s disease has been published (NEJM 2012; 367: 1519-28).

In this trial, members of CERTIFI (Crohn’s Evaluation of Response to Ustekinumab Anti-Interleukin-12/23 for Induction) from 153 centers in 12 countries assessed the efficacy of Ustekinumab in 526 adult patients.  The primary outcome was a clinical response (CDAI >100 point drop) at 6 weeks.

Ustekinumab (currently approved for plaque psoriasis) is a ‘fully human IgG1κ monoclonal antibody’ which blocks the activity of interleukin-12 (IL-12) and interleukin-23 (IL-23) by inhibiting receptors on T cells, natural killer cells, and antigen-presenting cells.  IL-12 and IL-23 have been implicated in the pathophysiology of Crohn’s disease.

This study of ustekinumab was a 36-week randomized, double-blind, placebo-controlled phase 2b trial.  The first 8 weeks were for induction.  After induction, based on response, patients were enrolled in a 28-week maintenance phase.  Initial dosing was 1, 3, or 6 mg/kg of intravenous ustekinumab or placebo.  Maintenance dose was 90 mg subcutaneously.

Patients were permitted to continue receiving stable doses of drugs.  However, entry requirements included a washout period for intravenous glucocorticoids (3 weeks), TNF antagonists (8 weeks), and natalizumab (12 months).

Results:

  • 36.6%, 34.1% and 39.7% of ustekinumab patients (1, 3, and 6 mg/kg respectively) responded at 6 weeks compared with 23.5% of placebo.  The difference was statistically significant for 6 mg/kg/dose.
  • Maintenance therapy (among responders) noted increased clinical remission with ustekinumab compared with placebo 41.7%  vs 27.4%.
  • Overall rates of infection were similar. Serious infections were noted in 6 patients receiving ustekinumab compared with 1 placebo-treated patient.  Infusion reactions were uncommon.
  • Patients who did not have a response to ustekinumab in the induction phase did not benefit from additional ustekinumab in the maintenance phase.

Overall, in this study, patients dosed at 6 mg/kg during induction were more likely to have a response but not more likely to have a remission.  Since all patients in this study had failed at least one TNF antagonist and 50% had failed at least two, the benefit of ustekinumab in other Crohn’s disease patients remains undefined.

Related blog entries:

CHOOSE TNF TRIAL | gutsandgrowth

Vedolizumab -another new IBD treatment | gutsandgrowth

Adding Methotrexate to anti-TNF therapy | gutsandgrowth

More “Survivin” in Crohn’s disease

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Survivin is a member of the inhibitors of apoptosis family.  It helps regulate cell division and prevents cell death.  (Gastroenterology 2012; 143: 1017-26).  While survivin has been shown to be important in cancer, it appears to be important in inflammatory and autoimmune disorders.

In the referenced study, lamina propria T cells (LPT) were isolated from mucosal samples of patients with Crohn’s disease (CD), ulcerative colitis (UC), and controls.  Expression of survivin was assessed by immunohistochemistry, confocal microscopy, and immunoblotting.

LPTs from patients with Crohn’s disease had increased survivin levels; this was not seen in control patients or UC patients.  Furthermore, the investigators showed that the survivin (bound to heat shock protein) was resistant to proteasome degradation.

Implications of this study: 

Survivin may have crucial consequences for CD and other inflammatory/autoimmune diseases; cell proliferation and apoptosis alteration may be important in the pathogenesis of  in these disorders.

Microbiome in pediatric ulcerative colitis

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Alterations in the gastrointestinal tract microbiome may play an important role in many digestive conditions.  A recent article examines microbiome alterations in children with severe ulcerative colitis (UC) (Inflamm Bowel Dis 2012; 18: 1799-1808).

Stool samples from 26 healthy children and 27 children with severe UC were prospectively studied.  After DNA extraction, PCR amplification and microarray hybirdization were performed and analyzed.   None of the patients in the study had received antibiotics or probiotics in the preceding month.

Key findings:

  • There were substantial reductions in “richness,” diversity, and evenness of the gut microbiome in UC patients.  (Richness is a term used to reflect the number of detected phylospecies.)
  • There was a decrease in signal in almost all  phylospecies.
  • The number of phylospecies was reduced in UC (266 ± 69) vs controls (758 ± 3)
  • Steroid responders had even fewer phylospecies compared with responders (142 ± 49  vs. 338 ± 62)

It is not surprising that the stools from these children are much different.  The issues of causation and whether a snapshot of the microbiome diversity will have clinical relevance is not clear.  It is possible that antimicrobials may make an individual more susceptible to inflammatory bowel disease by altering the individual’s microbiome.

Related blog entries:

Eat your veggies…if you don’t want to get sick | gutsandgrowth

Why are we seeing so many more cases | gutsandgrowth

Once daily Mesalamine

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Based on the literature, it is not clear that there is any need to give melamine more than once a day; this is often in contrast to labeling for many of these products:

  1. Inflamm Bowel Dis 2012; 18: 1785-94 
  2. Inflamm Bowel Dis 2012; 18: 1885-93

The 1st study identified 11 relevant randomized studies, after excluding 6870 that were considered irrelevant. Five of these studies were single blind and one was open-label; the remainder were double-blind randomized trials. In total, these studies examined 4070 patients.

Mesalamine products studied: Mesalazine (Salofalk), MMX mesalamine, Asacol, and Pentasa

Summary of findings:

  • Failure to induce clinical remission: relative risk (RR) with once daily 0.95; absolute risk 421 per 1000 in once daily group
  • Failure to induce clinical improvement: RR 0.87; absolute risk 398 per 1000
  • Failure to maintain clinical remission at 12 months: RR 0.92; absolute risk 286 per 1000
  • Failure to adhere to study medication regimen: RR 1.21; absolute risk 128 per 1000

Thus, this meta-analysis indicates that once daily dosing is as effective as conventional dosing for both induction and maintenance, at least with the formulations that were tested. Also, in this meta-analysis, adherence was not improved with once daily therapy, though some previous studies have indicated that once daily therapy may be helpful particularly in the first few months of treatment.

The 2nd study examined 213 patients for maintenance of UC remission; patients were randomized to receive either Asacol 2.4 g once a day (QD) or 800 mg three times a day (TID). Patients were treated at 32 UK centers and had an average age of 50 years. Relapse rates were 31% for QD therapy and 45% for TID over 1 year.  This study showed that QD was noninferior to TID and possibly superior, perhaps due to improved adherence.

Perhaps it is time to give all mesalamine products once a day.